KEYWORDS

Larotrectinib, a highly selective TRK kinase inhibitor, shows rapid, potent, and durable efficacy in both adult and pediatric patients with solid tumors that harbor TRK fusions, regardless of tumor type or patient age, according to results from three clinical trials published in the New England Journal of Medicine. The landmark data support the foundation of precision oncology by creating a treatment option for a genetically defined cancer while continuing to validate the concept that comprehensive molecular profiling should be strongly considered in people of all ages with advanced solid tumors.

Implications:

In December 2017, Loxo Oncology initiated the submission of a rolling new drug application to the Food and Drug Administration for larotrectinib, utilizing the same patient population and data cutoff as outlined in this paper. This is the first time that a targeted therapy has demonstrated consistent benefit across all tumor types that test positive for a specific mutation. In addition, this could lead to the first treatment developed and approved simultaneously for adult and pediatric patients.

Author Comments:

“The efficacy and durability of larotrectinib in this very diverse population is striking. No other targeted therapy has achieved such results through an age- and tumor-agnostic approach. Based on these data, we can say that individuals with TRK fusion–positive cancers have a treatment option, regardless of where the cancer began or the age of the patient,” said study co-corresponding author David Hyman, MD. “As the field of precision oncology evolves and we begin to identify tumor-agnostic biomarkers, such as TRK and MSI, we are seeing the necessity of next-generation sequencing. These data serve as further evidence that in the very near future, delivering the standard of care will require comprehensive genomic profiling for every cancer patient.”

“TRK fusions are consistently uncommon, meaning that while they are rare, they are widely distributed across both common and rare cancers, and they affect people of all ages,” explained study co-lead author Alexander Drilon, MD. “Not only do these findings credential TRK fusions as a therapeutic target and provide, for the first time, simultaneous data in adult and pediatric populations, they also continue to demonstrate the value of comprehensive molecular profiling in people with advanced solid tumors, regardless of tumor type.”

Findings:

Between March 2015 and February 2017, 55 patients (age four months to 76 years) with 17 unique TRK fusion–positive tumor types were treated across three clinical trials. The overall response rate was 75 percent by independent review and 80 percent by investigator assessment. The median time to response was 1.8 months, and the median duration of response and progression-free survival had not been reached as of the data cutoff in July 2017. Thirteen percent of participants achieved a complete response, 62 percent achieved a partial response, 13 percent had stable disease, and 4 percent were considered nonevaluable due to early withdrawal for clinical deterioration. At one year, 71 percent of responses were ongoing, and 55 percent of patients remained progression free. To date, 86 percent of responding patients remain on treatment or have undergone surgery with curative intent. Clinically significant adverse events were uncommon, with 93 percent of all adverse events being grade one or two.

Background:

TRK fusions are chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, or NTRK3) becomes abnormally connected to an unrelated gene. This abnormality results in uncontrolled TRK signaling, driving cancer growth. Although TRK fusions are rare in most individual cancers, in aggregate they represent thousands of people diagnosed each year, many of whom have limited treatment options. TRK fusions are thought to be present from the onset of these cancers, meaning that physicians can test patients early in order to identify this actionable mutation. One way to do this is through a genetic-sequencing test, such as the FDA-authorized MSK-IMPACT™ panel, which looks for alterations in more than 460 genes and can detect TRK fusions.

In recent years, Dr. Hyman and colleagues at MSK pioneered the concept of a basket trial, a type of research study that concentrates on a specific mutation found in a tumor. These studies have proven beneficial when researching rare cancers that are traditionally underrepresented in clinical trials. In addition, while pediatric drug development has historically been viewed as a burden due to the costs and risks associated with it, these trials have allowed for accelerated and simultaneous development in the adult and pediatric populations.

Initial data from these three clinical trials were presented at the American Society of Clinical Oncology’s 2017 annual meeting.

Method:

The efficacy of larotrectinib, a highly selective small molecule inhibitor of all three TRK kinases, was evaluated in an age- and tumor-agnostic development program across three multisite clinical trials. Patients with a locally advanced or metastatic TRK fusion-positive solid tumor were enrolled in one of three studies: an adult phase I trial, a pediatric phase I/II trial, or an adolescent/adult phase II trial. The primary endpoint for the combined analysis was overall response rate. Secondary endpoints included duration of response, progression-free survival, and safety. The decision to pool efficacy data across all three studies was made based on the rarity of TRK fusions and the inherent heterogeneity of cancer types.

Journal:

“Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children” was published in the New England Journal of Medicine on February 22, 2018.

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